The molecular programs underpinning ‘tolerance’ and ‘resistance’ in health and viral infection
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE184278 | GEO | 2022/12/27
REPOSITORIES: GEO
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Project description:The immune protection against invading pathogens is governed by pathogen elimination (‘resistance’) and by limitation of tissue damage that results from host-pathogen interactions (‘tolerance’). However, distinct molecular states of resistance and tolerance remain obscure. Here, we collected longitudinal lung transcriptomes and clinical phenotypes of disease severity during influenza A virus (IAV) infection across 39 genetically-distinct mouse strains (32 strains of time series data and additional 7 strains with selected time points). Using transcriptional diversity in this data, we uncovered two key programs that together describe the cellular states for resistance and tolerance. The identified programs offer an unprecedented comprehensive view on shared and distinct roles of resistance and tolerance for the regulation of immune defense – for instance, we identified an antagonistic regulation of resistance and tolerance on protein production. Importantly, the framework reveals that both inflammatory states and the healthy steady state are remarkably diverse in resistance and tolerance levels, with implications on disease severity: a baseline state (before infection) of high tolerance and low resistance results in increased severity of IAV infection. Overall, our work provides a framework for the study of resistance and tolerance that could aid in clinical diagnosis and disease management.
2022-12-27 | GSE174253 | GEO
Project description:The molecular programs underpinning ‘tolerance’ and ‘resistance’ in health and viral infection
| PRJNA763877 | ENA
Project description:The molecular programs underpinning 'tolerance' and 'resistance' in health and viral infection
| PRJNA728967 | ENA
Project description:The emergence of new highly pathogenic and drug-resistant influenza strains urges the development of novel therapeutics for influenza A virus (IAV). Here, we report the discovery of an anti-IAV microbial metabolite called APL-16-5 that was originally isolated from the plant endophytic fungus Aspergillus sp. CPCC 400735. APL-16-5 binds to both the E3 ligase TRIM25 and IAV polymerase subunit PA, leading to TRIM25 ubiquitination of PA and subsequent degradation of PA in the proteasome. This mode of action conforms to that of a proteolysis targeting chimera which employs the cellular ubiquitin-proteasome machinery to chemically induce the degradation of target proteins. Importantly, APL-16-5 potently inhibits IAV and protects mice from lethal IAV infection. Therefore, we have identified a natural microbial metabolite with potent in vivo anti-IAV activity and the potential of becoming a new IAV therapeutic. The antiviral mechanism of APL-16-5 opens the possibility of improving its anti-IAV potency and specificity by adjusting its affinity for TRIM25 and viral PA protein through medicinal chemistry.
2022-05-20 | PXD031993 | Pride
Project description:Viral infections affecting the upper or lower respiratory tract induce mucin production in the epithelial surfaces of the respiratory cells. However, a little is known about how mucins are produced on the surfaces of respiratory epithelial cells and affects viral replication. In the course of the investigation of the cellular responses in the early stage of Influenza A virus (IAV) infection, we found that two miRNAs, miR-221 and miR-17-3p, which target the mRNA of GalNAc transferase 3 (GALNT3), are rapidly down-regulated as early as 1.5 h post-infection. To understand the early host cell responses to the IAV infection, we performed miRNA microarray analysis using a human alveolar adenocarcinoma cell line, A549 cells, infected with influenza A/Puerto Rico/8/34 H1N1 (PR8) virus. We isolated the cellular RNAs at 0.5, 1.5 and 4.5 h post-infection and detected significant changes in the global profile of miRNA expression after infection with IAV. mouse embryonic fibroblasts. Each sample was run in duplicate.
2015-12-08 | E-GEOD-57508 | biostudies-arrayexpress
Project description:When challenged with an invading pathogen, host defense mechanisms are engaged to eliminate the pathogen (resistance) and limit tissue damage that results from host-pathogen interactions (disease tolerance). We identified Arhgdia as a driver of the molecular disease-tolerance response in epithelial cells. The effect of Arhgdia on disease tolerance and resistance was evaluated at early stages of influenza A virus (IAV) infection. Our observations indicates that Arhgdia has an effect on disease tolerance during IAV infection.
2022-12-27 | GSE193160 | GEO
Project description:An effective immune response to influenza A virus (IAV) requires two arms: host resistance, which restricts viral replication, and disease tolerance that limits tissue damage caused by the immune response to IAV. Interestingly, fatal influenza infections are more often associated with dysregulated inflammation, rather than an inability to control viral replication, highlighting the importance of mechanisms involved in disease tolerance to IAV. Here, we show that cyclophilin D (CypD), a mitochondrial protein known to regulate cell death and cytokine production, protects against IAV infection through disease tolerance. Mice deficient in CypD (CypD-/-) exhibit enhanced susceptibility to IAV infection, despite comparable myeloid immune responses and intact antiviral immunity. Instead, CypD-/- susceptibility was due to pulmonary tissue damage, caused by a lack of the cytokine IL-22 that protects the lung epithelium. We found the necessary source of IL-22 following IAV infection to be conventional natural killer (NK) cells that failed to reach the airways of infected CypD-deficient mice, as a result of dysregulated lymphopoiesis in the bone marrow. Importantly, following infection, a single administration of recombinant IL-22 in the airways abrogated pulmonary damage and rescued CypD-/- mice. Thus, the CypD/IL-22/NK cell axis is critical in immunity to IAV by promoting disease tolerance, limiting lung tissue damage and maintaining pulmonary function.
2022-06-21 | GSE163290 | GEO
Project description:Influenza A virus (IAV) infection causes acute respiratory disease with potential severe and deadly complications. Viral pathogenesis is not only due to the direct cytopathic effect of viral infections but also to the exacerbated host inflammatory responses. Influenza viral infection can activate various host signaling pathways that function to activate or inhibit viral replication. Our previous studies have shown that a receptor tyrosine kinase TrkA plays an important role in the replication of influenza viruses in vitro, but its biological roles and functional mechanisms in influenza viral infection have not been characterized. Here we show that IAV infection strongly activates TrkA in vitro and in vivo. Using a chemical-genetic approach to specifically control TrkA kinase activity through a small molecule compound 1NMPP1 in a TrkA knock-in (TrkA KI) mouse model, we show that 1NMPP1-mediated TrkA inhibition completely protected mice from a lethal IAV infection by significantly reducing viral loads and lung inflammation. Using primary lung cells isolated from the TrkA KI mice, we show that specific TrkA inhibition reduced viral RNA synthesis in airway epithelial cells (AECs) but not in alveolar macrophages (AMs). Transcriptomic analysis confirmed the cell-type-specific role of TrkA in viral RNA synthesis, and identified distinct gene expression patterns under the TrkA regulation in IAV-infected AECs and AMs. Among the TrkA-activated targets are various proinflammatory cytokines and chemokines such as IL6, IL-1, IFNs, CCL-5, and CXCL9, supporting the role of TrkA in mediating lung inflammation. Indeed, TrkA inhibitor 1NMPP1 administered after the peak of IAV replication, though had no effect on viral load, was able to decrease lung inflammation and provide partial protection in mice. Taken together, our results have demonstrated for the first time an important biological role of TrkA signaling in IAV infection, identified its cell-type-specific contribution to viral replication, and revealed its functional mechanism in virus-induced lung inflammation. This study suggests TrkA as a novel host target for therapeutics against influenza viral disease.
2022-09-05 | GSE203539 | GEO
Project description:Using influenza A virus (IAV) infection in a mouse model of naturally selected genetic diversity, namely C57BL6/J (B6) mice carrying chromosomes (Chr) derived from the wild-derived and genetically divergent PWD/PhJ (PWD) mouse strain (B6.ChrPWD consomic mice), we examined the effects of genotype and sex on severity of IAV-induced disease To determine the role of genetic variation of host during IAV infection on gene expression, we performed RNAseq analysis on whole lung RNA isolated from two different mice.
2022-08-13 | GSE210905 | GEO
Project description:Influenza A virus (IAV) is a human respiratory pathogen that causes yearly global epidemics, and sporadic pandemics due to human adaptation of pathogenic strains. Efficient replication of IAV in different species is, in part, dictated by its ability to exploit the genetic environment of the host cell. To investigate IAV tropism in human cells, we evaluated the replication of IAV strains in a diverse subset of epithelial cell lines. HeLa cells were refractory to growth of human H1N1 and H3N2, and low pathogenic avian influenza (LPAIs) viruses. Interestingly, a human isolate of the highly pathogenic avian influenza (HPAI) virus H5N1 successfully propagated in HeLa cells to levels comparable to a human lung cell line. Heterokaryon cells generated by fusion of HeLa and permissive cells supported H1N1 growth, suggesting the absence of a host factor(s) required for replication of H1N1, but not H5N1, in HeLa cells. The absence of this factor(s) was mapped to reduced nuclear import, replication, and translation, and deficient viral budding. Using reassortant H1N1:H5N1 viruses, we found that the combined introduction of nucleoprotein (NP) and hemagglutinin (HA) from H5N1 was necessary and sufficient to enable H1N1 growth. Overall, this study suggests the absence of one or more cellular factors in HeLa cells that results in abortive replication of H1N1, H3N2, and LPAI viruses, but can be circumvented upon introduction of H5N1 NP and HA. Further understanding of the molecular basis of this restriction will provide important insights into virus-host interactions that underlie IAV pathogenesis and tropism.
2019-11-21 | GSE140759 | GEO